Many therapeutic agents are most effective when present at a uniform concentration in the blood. They may be ineffective at a lower level and toxic at a higher level, causing, for example, cardiac, kidney or hearing injury. A reasonably constant, effective and safe blood level may be achieved by intravenous infusion of a uniform solution of the drug directly into the blood. This is not practical in most situations such as veterinary medicine, long term medication, and ambulatory health care outside of the hospital, where oral dosage formulations may achieve a therapeutic effect. A single daily dose will generally cause the blood level to rise to a peak and then fall off as the drug is first absorbed into the blood and then excreted or metabolized. To achieve a more uniform blood level, the drug may be administered in divided doses over timed intervals throughout the day, to produce a pulsatile blood concentration curve with time. In some situations this may be more effective than a uniform blood level. It is inconvenient to take many dosage units throughout the day. It may also be more prone to error from missed doses and double doses.
U.S. Pat. No. 4,851,229 issued Jul. 25, 1989 to Magruder et al. discusses relative merits of steady state versus pulsatile drug delivery regimens and discloses a unit dosage form of complex structure for pulsatile delivery of drug employing an osmotic pump mechanism and a semi permeable shell with a tiny hole in the shell through which the drug is ejected.
Magruder discloses that a wide choice of different modulating or osmotic agents are available and well known in the art, as follows (Col 6 line 35) "The modulating agents useful for the purpose of this invention are soluble in aqueous and biological fluids, such as ionizing compounds, inherently polar compounds, inorganic acids, organic acids, bases and salts, and salts containing a common ion with the drug. In a preferred embodiment the compounds are solids and they dissolve and form a solution with fluids imbibed into the osmotic device. Examplary inorganic salts are represented by a member selected from the group consisting essentially of lithium chloride, lithium sulfate, magnesium chloride, magnesium sulfate, potassium chloride, potassium sulfate, potassium acid phosphate, sodium chloride, sodium sulfate, sodium sulfite, sodium nitrate, sodium nitrite, and the like. Salts of organic acids are represented by a member selected from the group consisting essentially of sodium citrate, potassium acid tartrate, potassium bitartrate, sodium bitartrate, and the like."
U.S. Pat. No. 5,001,692 issued Apr. 30, 1991 to Fujioka et al. discloses a preparation with multiple layers for a pulsatile release effect.
U.S. Pat. No. 5,017,381 issued May 21, 1991 to Maruyama et al. discloses a plurality of cup shaped elements within a housing to provide a pulsatile delivery system.
These systems require special manufacturing procedures and equipment for the special structures that are costly and may be less reliable than conventional pharmaceutical manufacturing procedures. They may not be as readily controlled for particular time intervals. They are not readily adapted to a large number of pulses in a single dosage form as may be most desirable in a rapidly absorbed and excreted drug having a short useful half-life in the blood.